The incidence of diabetes mellitus (diabetes) is rising years by years. This disease seriously harms the health of human being. In the patients having diabetes mellitus, most of them are the type II (i.e. noninsulin-dependent) diabetic patient, who is characterized by the insulin resistance. The hyperglycemia is a sign of the type II diabetes mellitus, and is considered as a major risk factor for forming a complication of diabetes mellitus. Currently, the clinically-used anti-diabetic drug mainly includes dimethyl biguanides, sulfonyl ureas, and insulin sensitivity enhancers. Dimethyl biguanides and sulfonyl ureas occasionally show the side-effects such as lactic acidosis and hypoglycemia. Insulin sensitivity enhancers occasionally show the side-effects such as edema and obesity. The newly marketed anti-diabetic drugs include the drugs such as thiazolidinediones and α-glucosidase inhibitors. These drugs have good therapeutic effects, but still have the safe problem if administered for a long term. Therefore, in order to solve these problems, there is a need to develop the anti-diabetic drug having a new action mechanism.
Sodium-dependent glucose cotransporter (SGLT) is a new target that is discovered recently and used for treating diabetes mellitus. It can be divided into two sub-types, SGLT-1 and SGLT-2. SGLT-2 is a protein composed of 672 amino acids and containing 14 transmembrane segments; and is mainly expressed in the first 51 segments of the proximal renal tubule. SGLT-1 is distributed in small intestine, heart and kidney. SGLT-2 absorbs 90% of glucose in the primary urine. Only 10% of glucose is recycled to the body by the SGLT-1 absorption. It is promising for the selective inhibition of SGLT-2 to normalize the glucose in the blood plasma by increasing the urine glucose excretion, so as to increase the insulin sensitivity and retard the development of the complication of diabetes mellitus. Because the SGLT-2 inhibitor is not involved in the glucose metabolism, therefore it can be used as the supplementary means for the main method of controlling the blood glucose. Therefore, it is urgently desired to develop an anti-diabetic drug that has a strong inhibitory activity on SGLT-2 and has the new action mechanism. It is believed that this drug may reduce or prevent obesity while it promotes the excretion of the excessive glucose through the urine and therefore reduce the accumulation of glucose in the body.
A study shows that a glucose derivative, phlorizine, which is separated from nature substance and has a structure as shown below, may hinder the re-absorption of the excessive glucose in the kidney, promote the excretion of the glucose, and have an effect of reducing the blood glucose (Rossetti, L., et al. J. Clin. Invest., Vol. 80, page 1037, 1987; Vol. 79, page 1510, 1987). By modifying the structure of phlorizine, the related analogues can be divided into O-carbocyclic glycoside derivative, O-heterocyclic glycoside derivative, C-carbocyclic glycoside derivative, C-heterocyclic glycoside derivative, N-glycoside derivative, and the like. As a specific inhibitor for SGLT-2, phlorizine or the above closely related analogues can promote the excretion of the glucose but have no side effect of low blood glucose. They can inhibit the glucose re-uptaking in the experiment with dogs suffering from diabetes mellitus, and therefore cause the glucose level in the plasma to normalize.

It is reported that upon the oral administration of O-carbocyclic glycoside derivative or O-heterocyclic glycoside derivative, the glucoside bond is hydrolyzed by the β-glycosidase present in the small intestine, and there is a poor absorption efficiency for the glycoside derivative in its original form (Ehrenkranz, J. R., Lewis, N. G., Kahn, C. R. & Roth, J. Phlorizin: a review. Diabetes Metab. Res. Revs. 21, 31-38 (2005)).
WO 01/27128 (Bristol-Myers Squibb) discloses a compound represented by the following structure:
wherein A is O, S, NH or (CH2)n, n is 0-3; R1, R2 and R2a are independently H, OH, alkyl, CF3, OCHF2, OCF3, halogen or the like; R3 and R4 are independently H, OH, O-aryl, OCH2-aryl, alkyl, cycloalkyl, CF3, —OCHF2, —OCF3, halogen, or like. It is reported that these compounds are the inhibitors of the SGLT-2 transport protein, and therefore represent an approach for treating diabetes mellitus and its complications.
WO 2003/099836 (Bristol-Myers Squibb) further discloses a SGLT-2 inhibiting compound, which has a structure as shown below and is subsequently named as dapagliflozin:

This application teaches a method of treating diabetes mellitus and the related diseases by administering a SGLT-2 inhibitory amount of the above compound alone or in combination with other anti-diabetic agents or other therapeutic agents. It is also reported that Dapagliflozin is a SGLT-2 inhibitor having a good selectivity, and has an IC50 value on the human SGLT-2 of 1.12 nM and an IC50 value on the human SGLT-1 of 1391 nM (Diabetes 57:1723-1729, 2008). Dapagliflozin is now in the stage III clinical trial, and has an effect of regulating the glucosuria, controlling the blood glucose and reducing the body weight. Its side effect mainly includes the hypoglycemia and the vaginal infection.
WO 98/31697 discloses a compound represented by the following structure:
wherein Ar can be an aryl having 6-18 carbon atoms, including phenyl, biphenyl, diphenylmethane, diphenylethane and diphenylether, and R1 is glycoside, R2 is H, OH, amino, halogen, carboxyl, alkyl, cycloalkyl or the like, R3 is hydrogen, alkyl or acyl, and each of k, m and n is independently 1-4. It is said that the disclosed compound can be used to treat or prevent inflammatory diseases, autoimmune diseases, infections, cancer and cancer metastasis, reperfusion disorders, thrombosis, ulcer, wounds and osteoporosis.
WO 2005/012326 discloses a compound represented by the following structure:
wherein Ring A and Ring B can be: Ring A is an optionally substituted benzene ring; and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring or an optionally substituted unsaturated fused heterobicyclic ring; X is a carbon atom or a nitrogen atom; Y is —(CH2)n—, wherein n is 1 or 2. The compound disclosed in this PCT application comprises a compound with the following structure:
wherein Ring A is an optionally substituted benzene ring; and Ring B is an optionally substituted unsaturated monocyclic heterocyclic ring or an optionally substituted unsaturated fused heterobicyclic ring. It is said that the disclosed compound can be used as the SGLT-2 inhibitor. This application further discloses a SGLT-2 inhibiting compound, which has the following structure:
and subsequently named as Canagliflozin. It is also reported that Canagliflozin has an IC50 value on the human SGLT-2 of 2.2 nM and an IC50 value on the human SGLT-1 of 910 nM (J. Med. Chem., 2010, 53, 6355-6360), and can remarkably increase the urine glucose level by inhibiting SGLT-2 so as to accomplish the treatment effect. Canagliflozin has a high oral bioavailability, and can effectively improve the glucose level in the patient and reduce the body weight. It is indicated by the research data that those diabetic patients, who got less therapeutic effect by treating with dimethyl biguanide (Metformin) alone, have got better therapeutic effect by treating with Canagliflozin and Metformin in combination, which is benefited from the action mechanism of the drug inhibiting SGLT-2.
WO 2008/042688 discloses a compound represented by the following structure:
wherein A is optionally substituted aryl, cycloalkyl or heterocycle; X is O, S or NR3; when X is O, R1 is OR1A, SR1A, SOR1A, SO2R1A or N(R1A)2; when X is S, R1 is hydrogen, OR1A, SR1A, SOR1A or SO2R1A; when X is NR3, R1 is OR1A, SR1A, SOR1A, SO2R1A, or R1A; wherein each R1A is independently hydrogen or optionally substituted alkyl, aryl or heterocycle; R2 is fluoro or OR2A; each of R2A, R2B and R2C is independently hydrogen, or optionally substituted alkyl, C(O)alkyl, C(O)aryl or aryl; R3 is hydrogen, C(O)R3A, CO2R3A, CON(R3B)2, or optionally substituted alkyl, aryl or heterocycle; each R3A is independently optionally substituted alkyl or aryl; and each R3B is independently hydrogen or optionally substituted alkyl or aryl. The compound disclosed in this application comprises a compound with the following structure:

Wherein each of R6 and R2 is independently hydrogen, hydroxyl, halogen, amino, nitro, C CR6A, OR6A, SR6A, SOR6A, SO2R6A, C(O)R6A, CO2R6A, CO2H, CON(R6A) (R6A), CONH(R6A), CONH2, NHC(O)R6A, NHSO2R6A, or optionally substituted alkyl, aryl or heterocycle; wherein R6A is optionally substituted alkyl, aryl or heterocycle; m is 1-3; and n is 1-3. It is said that the disclosed compound can be used to treat diabetes mellitus and obesity.
In summary, it is a hotspot in the current anti-diabetic research to seek for a specific SGLT-2 inhibitor with a high efficiency and a low toxicity.